Often a mixing process produces a large ‘bulk’ of mixture that is subsequently subdivided into individual dose units (e.g. a tablet, capsule or 5 mL spoonful), and it is important that each dosage unit contains the correct amount/concentration of active component(s). It is the weight/volume of the dosage unit which dictates how closely the mix must be examined/analysed to ensure it contains the correct dose/concentration. This weight/volume is known as the scale of scrutiny and is the amount of material within which the quality of mixing is important. For example, if the unit weight of a tablet is 200 mg, then a 200 mg sample from the mix should be analysed to see if mixing is adequate; the scale of scrutiny therefore being 200 mg. If a larger sample size than the scale of scrutiny is analysed, this may mask important micro-nonuniformities such as those caused by agglomerates and may lead to the acceptance of an inadequate mix. Conversely, analysing too small a sample size may lead to the rejection of an acceptable mix.

random powder mix with different numbers of particles in the scale of scrutiny

The number of particles contained in the scale of scrutiny will depend on the sample weight, particle size and particle density, and will increase as the sample weight increases and the particle size and density decrease. This number should be sufficient to ensure an acceptably small deviation from the required dose in the dosage forms.

Another important factor to consider when carrying out a mixing process is the proportion of the active component in the dosage form/scale of scrutiny. This is illustrated in Fig. 1 and Table 1, the latter also demonstrating the importance of the number of particles in the scale of scrutiny.

Fig. 1 shows a random mix containing only 10% coloured particles (active ingredient). If the blocks of 25 particles are examined, it can be seen that the number of coloured particles varies from 0 to 8, or 0% to 32%. Thus the number of coloured particles as a percentage of the theoretical content varies from 0% to 320%. This is considerably greater than the range of 48% to 152% when the proportion of coloured particles was 0.5 or 50%.

Table 1 shows how the content of a minor (potent) active constituent (present in a proportion of 1 part in a 1000, i.e. 0.1%) typically varies with the number of particles in the scale of scrutiny, when sampling a random mix. In the example shown, when there are 1000 particles in the scale of scrutiny, three samples contain no active constituent and two have twice the amount that should be present.

With 10 000 particles in the scale of scrutiny, the deviation is reduced but samples may still deviate from the theoretical content of 10 particles by ±50%. Even with 100 000 particles, deviation from the theoretical content may exceed ±15% which is generally unacceptable for a pharmaceutical mixture. The difficulty in mixing potent substances can be appreciated if it is realized that there may only be approximately 75 000 particles of diameter 150 µm in a tablet weighing 200 mg.

1. The information in Figs 1 and Table 1 leads to two important conclusions:
   The lower the proportion of active component present in the mixture, the more difficult it is to achieve an acceptably low deviation in active content.
2. The more particles there are present in a unit dose/scale of scrutiny, the lower the likely deviation in content.

One way of reducing the deviation, therefore, would be to increase the number of particles in the unit dose by decreasing the particle size. This may, however, lead to particle agglomeration due to the increased cohesion and adhesion that occurs with smaller particles, which in turn may reduce the ease of mixing.

Reference:

• Aulton, M. E., & Taylor, K. (2018). Aulton’s Pharmaceutics: The Design and Manufacture of Medicines, 5th ed. Elsevier.